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Rapid up-regulation of mdr1 expression by anthracyclines in a classical multidrug-resistant cell line
1Department of Medical Oncology, Heidelberg Repatriation Hospital, Victoria, Australia.
Abstract:
Studies were carried out in a variant human multidrug-resistant (MDR) cell line CEM/A7R, which expresses very low levels of mdr1 mRNA and P-glycoprotein (P-gp). The induction of mdr1 RNA expression by three anthracyclines, (doxorubicin, daunorubicin, epirubicin), VP-16 and two vinca alkaloids (vincristine, vinblastine) was semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of mdr1 expression was expressed as ratio of mdr1 to the internal RNA (actin). A significant increase (P < 0.02) in expression of mdr1 was noted within 4 hrs of exposure to 1.5 micrograms ml-1 daunorubicin or epirubicin. Neither vinblastine nor vincristine had any effect on mdr1 levels after an 8 h exposure. With increasing concentrations of daunorubicin or epirubicin in a fixed 24 h time period, mdr1 expression increased, although a biphasic response was seen. Based on MRK 16 binding, an increase in P-gp levels was seen in the CEM/A7R line after a 24 h exposure to 1 microgram ml-1 daunorubicin or epirubicin. The rapid increase in mdr1 expression after a short period of exposure to doxorubicin, daunorubicin or epirubicin suggests that induction of mdr1 expression may have an important role in the development of drug-resistant tumours.
Insights
Certain chemotherapy drugs rapidly increase multidrug resistance (MDR) gene expression in cancer cells. This rapid mdr1 gene induction by anthracyclines suggests a role in developing drug-resistant tumors.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
- The CEM/A7R cell line exhibits low basal expression of mdr1 mRNA and P-glycoprotein (P-gp).
Purpose of the Study:
- To investigate the induction of mdr1 gene expression by various chemotherapy drugs in the CEM/A7R cell line.
- To assess the role of P-glycoprotein (P-gp) in multidrug resistance.
Main Methods:
- Semiquantitative assessment of mdr1 RNA expression using scanning Northern blots and phosphorimaging.
- Analysis of P-gp levels via MRK 16 binding.
- Exposure of CEM/A7R cells to anthracyclines (doxorubicin, daunorubicin, epirubicin), VP-16, and vinca alkaloids (vincristine, vinblastine).
Main Results:
- Daunorubicin and epirubicin significantly increased mdr1 expression within 4 hours (P < 0.02).
- Vinca alkaloids did not affect mdr1 levels after 8 hours.
- Increased P-gp levels were observed after 24-hour exposure to daunorubicin or epirubicin.
Conclusions:
- Rapid induction of mdr1 expression by anthracyclines suggests a key role in the development of drug-resistant tumors.
- Understanding mdr1 gene regulation is crucial for overcoming chemotherapy resistance.